new drugs and strategies for hcv treatment january_02_puoti.pdfnew drugs and strategies for hcv...
TRANSCRIPT
New drugs and strategies for HCV treatment
Massimo Puoti
SC Malattie Infettive
AO Ospedale Niguarda Cà Granda, Milano
New drugs and strategies for HCV treatment
• Tools & strategies
• Upcoming Results
• The future
New drugs and strategies for HCV treatment
• Tools & strategies
• Upcoming Results
• The future
Role of HCV eradication (Sustained Virologic Response X ) in the natural
history of HCV related diseases
HCV
B lymph stimulation
Liver Damage
ChronicInflammation & Metabolic effect
Immune Complexes related
diseases
Cryoglobulinemia Lymphoproliferativediseases
Fibrosis Progression
Cirrhosis w/o Portal
Hypertension
Cirrhosis with Portal
Hypertension
DecompCirrhosis
HCC
OsteoporosisDiabetes
Cardiovascular disesase
NephropathyNeuropathy
Reduced quality
of lifeReduced survival
CO - FACTORS
CO - FACTORS
X(?)X(?)
X(?)X(?)
X(?)
X(?)
X(?)
X
X
X
X
XX
Sustained Virologic Response: a gamebreaker for HCV patients
• Improvement in non cirrhotics• Non progression to cirrhosis
• Reduced incidence of extrahepatic manifestations
• B Cells Lymphomas
• Cryoglobulinemia
• Diabetes
• Neurocognitive function improvement
• Overall survival
• Improvement in compensated cirrhotics• Reduced incidence of Clinical decompensation and Variceal bleeding
• Reduced incidence of Hepato Cellular Carcinoma (HCC)
• Cirrhosis Regression in pts w/o Portal Hypertension
• Liver related survival
• Improvement in decompensated cirrhotics ???
Aghemo A et al J Hepatol 2012; 57: 1326-35
The number needed to treat to prevent mortality andcirrhosis-related complications within 5 years among patients with cirrhosis and HCV genotype 1 infection (eligible for Interferon)
SVR % NNT to prevent all causes mortality
(95% CI)
NNT to prevent cirrhosis related
complications (95% CI)
35% 61 (54-101) 18 (16-24)
50% 43 (38-71) 13 (11-17)
85% 25 (23-42) 8 (7-10)
95% 23 (20-37) 7 (6-9)
From Van der Meer AJ et al. J Viral Hepatitis 2013 modified
miRNA
ISIS 14803 (antisense)
AVI- 4066 (antisense)
Heptazyme (ribozyme)
VGX-410C (small molecules IRES
inhibitor) TT 033 (sIRNA)
eIF2a phosphorilation inhibitors:
Nitazoxanide
Lindenbach BD & Rice CM. Nature 2005;436:933–938; Moradpour D & Penin F. Curr Top Microbiol Immunol 2013;369:113–142.
HCV targets for therapy
Core
Virion assembly
Translation and processing
of polyprotein RNA replication
Receptors binding
And endocytosis
Fusion and
decapsidation
(+) RNA
Transport and release
4A NS4B NS5AE2E1C p7 NS2 NS3 NS5B
NS3 protease
Serine protease
domain
NS2–NS3
protease
Core Membrane RNA-dipendent RNA
polymerase
“entry inhibitors”
mAbs anti-E2/CD81,
PRO 206 Ezetimibe
Traslation
Protease inhibitorsReplication
inhibitors:
•NS5B
•NNI,
• NI
•NS5A I
•Ciclophyllin B
Inhibitors of
viral
assembly and
relaese :
Celgosivir
NS5A I
Drugs active on viral enzymes
Drugs active on host cell enzymes
HCV: probability of the presence of viral variants
Number of
nucleotide
change
Probability of
generation after
one round of
replication
Number of
virions with
nucleotide
change(s)
produced per
day
Number of all
possible
nucleotide
mutants
Fraction of all
possible
mutants created
per day
0 91% 9.1 x 1011
1 8.7% 8.7 x 1010 2.9 x 104 1
2 0.4% 4.2 x 109 4.1 x 108 1
3 0.001% 1.3 x 108 4.0 x 1012 3.4 x 10-5
Hepatitis C virus: ~9600 nucleotidesError rate during replication: ~10-4 – 10-5 per copied nucleotideViral turnover: ~1012 virions produced every day
Not all variants survive- Dead mutations (variants that can not replicate)- Immune sensitive mutations (variants eliminated by the immune system)
Rong L, et al. Sci Transl Med 2010;2:30ra32; Neumann AU, et al. Science 1998;282:103–107Domingo E, et al.. Viral Hepatitis Rev 1996;2:247–261; Cuevas JM, et al. J Virol 2009;83:5760–5764
Resistant virus Sensitive virus
Drug potency
Resistance
barrier
Intracellular drug concentrations
IC50 of mutant viruses
N of mutations needed to reduce IC50
Fitness of mutant viruses
Emergence of pre-existing resistant variants during treatment with DAA
DAA classes and subclasses
Drug Class Subclass Potency Resistance barrier
Protease inhibitors“- previr”
1st Generation first wave i.e. Telaprevir/Boceprevir
Medium-Low
Low
1st Generation 2nd wave i.e. Simeprevir/Asunaprevir Paritaprevir/r
Medium Low
2nd GenerationGrazoprevir (in vivo) ABT 493 (in vitro)
High High except HCVG3
NS5a inhibitor“ ..asvir”
1st GenerationDaclatasvir, Ledipasvi,r Ombitasvir, Elbasvir
High Medium- High except HCV G3 &
1a
2nd Generation GS 5816 (in vivo) ABT530 (in vitro)
High High
Ppolymerase inhibitors “..buvir”NN
DasabuvirBeclobuvir
Low-Medium
Low
Nucleos/tides 2nd Generation : Sofosbuvir High High
10
Consequences of HCV variability at population level: HCV genotypes
0% <1% 1-5% 5-10% 10-25% >25%
Amino acid variability:
47% amino acid of
HCV PROTEASE NS3 are
conserved among All HCV-
genotypes
54.8% amino acid of HCV
POLYMERASE NS5B are conserved
among All HCV-genotypes
0% <1% 1-5% 5-10% 10-25% >25%
Amino acid variability:
46.1% amino acid of
HCV NS5A are
conserved among All
HCV-genotypes
Cento V, et al. PLoS ONE 2012;7(7):e39652 Love RA, et al. J Vir 2009;83(9):4395–4403 Di Maio VC, et al. Antimicrob Agents Chemother 2014;58(5):2781–97
HCV protein variability
DAA classes and subclasses: antiviral potency and resistance barrier according to HCV genotype
Drug Class Subclass1 b 1a 2 3 4
Protease inhibitors
1st Generation first wave i.e.
Telaprevir/Boceprevir
1st Generation 2nd wave i.e.
Faldaprevir/Simeprevir
2nd Generation
MK5172 ABT 493
NS5a Inhibitor
1st Generation
Daclatasvir Ledipasvir Ombitasvir
2nd Generation
MK 8742 GS 5816 ABT 530
NN Polymerase
Inhibitors
Dasabuvir Deleobuvir
Nucleos/tides
Polymerase
inhibitors
2nd Generation : Sofosbuvir
13 High Moderate Low Very low
Time on treatment weeks
Combo with PEGIFN + RBV of 1 DAA low resistance barrier (Boceprevir, Simeprevir and Daclatasvir)
Potent IFNa-ribavirin effect
DAA Monotherapy
-5
-4
-3
-2
-1
0
1
Wild-type, sensitive HCV
Resistant HCV
Me
dia
n H
CV
RN
A c
han
ge
fro
m b
ase
line
(lo
g 10
IU/m
L)
Triple Combo
Sarrazin C et al J Hepatol. 2012;56 Suppl 1:S88-100.
Combo with PEGIFN + RBV of 1 DAA low resistance barrier (Boceprevir, Simeprevir and Daclatasvir)
-5
-4
-3
-2
-1
0
1
Wild-type, sensitive HCV
Resistant HCV
Time on treatment
Med
ian
HC
V R
NA
ch
an
ge
fro
m b
aselin
e (
log
10
IU/m
L)
Weak IFNa-ribavirin effect (IL28 TC/TT /Cirrhosis /PR failures)
Triple ComboPredictive role of RVR and Response
Guided Therapy
Sarrazin C et al J Hepatol. 2012;56 Suppl 1:S88-100.
DAA Monotherapy
Anchor drug monother
-5
-4
-3
-2
-1
0
1
Wild-type, sensitive HCV
Resistant HCV
Time on treatment
Combo with PEG IFN & RBV + 1 high resistance barrier DAA (Sofosbuvir)
Media
n H
CV
RN
A c
hange
from
base
line (
log
10
IU/m
L)
Any IFNa-ribavirin effect
Triple ComboNo Predictive role of RVR
No Response guided therapy
Sarrazin C et al J Hepatol. 2012;56 Suppl 1:S88-100.
Anchor drug monother
-5
-4
-3
-2
-1
0
1
Wild-type, sensitive HCV
Resistant HCV
Time on treatment
1 high resistance barrier DAA (Sofosbuvir) +Ribavirin + 1 DAA x 12-24 weeks
Media
n H
CV
RN
A c
hange
from
base
line (
log
10
IU/m
L)
Treatment duration & Ribavirin use
Triple ComboHCV Genotype & Cirrhosis/PR exp guided therapy
No Predictive role of RVR
No Response guided therapy
Sarrazin C et al J Hepatol. 2012;56 Suppl 1:S88-100.
Anchor drug monother
-5
-4
-3
-2
-1
0
1
Wild-type, sensitive HCV
Resistant HCV
Time on treatment
2-3 low resistance barrier DAA + Ribavirin x 12-24 weeks
Media
n H
CV
RN
A c
hange
from
base
line (
log
10
IU/m
L)
Treatment duration & Ribavirin use
Triple ComboHCV Genotype & Cirrhosis/PR exp guided therapy
No Predictive role of RVR
No Response guided therapy
Sarrazin C et al J Hepatol. 2012;56 Suppl 1:S88-100.
Anti HCV Drugs Prices x treatment cycle
Drug US Price $ EU lowest price €
Price for Italian NHS €
Sofosbuvir 84-168.000 39-68.000 X?-37.000
Daclatasvir 15.6 – 31.200 ?
Simeprevir 54.000 18.000 (?)
Harvoni 94-188.000 45-90.000 ?
Viekira Pack 83-166.000 ?
2520 - 5040 $
Strategies of DAA based HCV eradication
• IFN/Riba based• IFN/Riba based (HCV G1 & 4)
• IFN + 1 DAA with low resistance barrier
• Sofosbuvir based• IFN/riba + Sofosbuvir (1 DAA high resistance barrier)
• Sofosbuvir (high resistance barrier) + RBV
• Sofosbuvir (high resistance barrier) + 1 DAA + RBV
• Sofosbuvir free• 3 (2) DAAs low resistance barrier
• Sofosbuvir based “pangenotypic”• Sofosbuvir + 1/2 DAA Pangenotypic
• Sofosbuvir free “pangenotypic”• 2 DAA pangenotypic
Adjusted for HCV
GenotypePrevious Tx
for HCVCirrhosis
Fine tuning by RBV & Tx duration
One pill for all
Phase IV
Phase II-III
New drugs and strategies for HCV treatment
• Tools & strategies
• Upcoming Results
• The future
Summary of SVR rates to IFN based regimens in HCV G1 HIV- Naives Non Cirrhotics
Lawitz E, et al. NEJM 2013; Jacobson et al. AASLD 2013; Yoshida et al. AASLD 2013.
89.35
82.0272.44
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
90.00
100.00
SOFO G1 SIME G1 FALDA G1
506291 1045
% o
f tr
eate
d p
ati
ents
wit
h S
VR 1
2 (
95% C
I)
PR + SOFO
X 12 wPR + SIME
X 24 w
A
B
C
D
PEG IFN + RBV + SOFO vs PEG IFN + RBV + SIME SVR12 according to Rapid Viral Response (RVR) to PEG IFN + RBV + SIME and fibrosis stage
PEG IFN + RBV + SIMERVR ( HCVRNA undetectable < 25 IU/mL at 4 weeks)
All 404 /509: 79% (95 % CI 76-83%)F3-F4 88/130: 68% ( 95% CI 50-76%)
291 509 404 220 79 130 88
Lawitz E, et al. NEJM 2013; Jensen et al. AASLD 2013; Yoshida et al. AASLD 2013.
89.3582.02
89.6091.82
83.54
68.46
81.82
0.00
20.00
40.00
60.00
80.00
100.00
120.00
SOFO G1 ALL
SIME G1 ALL
SIME G1 WITH RVR
SIME G1b WITH RVR
SOFO G1 F3-F4
SIME G1 F3-F4
SIME G1 F3F4 with
RVR
% o
f tr
eate
d p
ati
ents
wit
h S
VR 1
2 (
95% C
I)
0
10
20
30
40
50
60
70
80
90
100
1 2
Summary of SVR rates to IFN based regimens in HCV G1 HIV- Experienced Non Cirrhotics
PR + SOFO Pol Easl 2014; TRIO AASLD 2014
PR SIME: ATTAIN study Reddy APASL 2013
PR + SOFO
X 12 w
PR + SIME
X 48 w
78%
87 379
54%
A
B
C
D
80.77
60.42
47.06
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
90.00
100.00
SOFO G1 CIRR SIME G1 CIRR FALDA G1 CIRR
% o
f tr
eate
d p
ati
ents
wit
h S
VR 1
2 (
95% C
I)
Lawitz E, et al. NEJM 2013; Jensen et al. AASLD 2013; Yoshida et al. AASLD 2013.
52 48 85
Summary of SVR rates to IFN based regimens in HCV G1 HIV- Naives Cirrhotics
A
B
C
D
PR + SOFO
X 12 w
PR + SOFO
X 12 w
PR + SIME
X 12 w
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4 5
Summary of SVR rates to IFN free regimens in HCV G1 HIV- and HIV+ Naives non Cirrhotics
SIM/SOF study Cosmos, cohorts: TRIO, TARGET
SOF/LED studies ION-1 ION-3
3D: studies PEARL SAPPHIRE
SOFO + R: SPC Sovaldi
SOF/SMV
+R
X 12-24s
SOF/DAC
+R
X 12-24s
SOF/LEDI
+R
X 12-24s
3D +R
X 12-24s
94% 99% 98% 96%
214 126 729 1380
SOFO +R
X 24s
148
68%
A
B
C
D
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4
Summary of SVR rates to IFN free regimens in HCV G1 HIV- Experienced non Cirrhotics
SIM/SOF study Cosmos, cohorts: TRIO, TARGET
SOF/LED studies ION-1 ION-3
3D: studies PEARL SAPPHIRE
SOFO + R: SPC Sovaldi
SOF/SMV
+R
X 12-24s
SOF/DAC
+R
X 12-24s
SOF/LEDI
+R
X 12-24s
3D +R
X 12-24s
87% 100% 98% 96%
144 41 350 472
A
B
C
D
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4
Summary of SVR rates to IFN free regimens in HCV G1 HIV- Naives Cirrhotics
SIM/SOF study Cosmos, cohorts: TRIO, TARGET
SOF/LED study meta analysis AASLD 2014
3D: studies Turquoise II
SOF/SMV
+R
X 12-24 w
SOF/LEDI
+R
X 12-24 w
3D +R
X 12-24 w
87% 98% 94%
246 161 160
A
B
C
D
SOF + R
X 124 w
11
36%
0
10
20
30
40
50
60
70
80
90
100
1 2 3
Summary of SVR rates to IFN free regimens in HCV G1 HIV- Experienced Cirrhotics
SIM/SOF study Cosmos, cohorts: TRIO, TARGET
SOF/LED study meta analysis AASLD 2014
3D: studies Turquoise II
SOF/SMV
+R
X 12-24 w
SOF/LEDI
+R
X 12-24 w
3D +R
X 12-24 w
85% 95% 90%
158 352 141
A
B
C
D
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4 5 6 7
Summary of SVR rates in HCV G2 HIV-
Registrative studies: Fusion, Fission Positron, Valence, Lonestar,
cohorts: TRIO, TARGET
SOF+R
X 12 w
94% 81% 90%
415 282 14
A
B
C
D
PR §X 24 w
81
SOF+R
X 12 w
Naïve Exp
Non Cirrhosis
89%
SOF+R
X 12 w
87%
109
PR §X 24 w
13
SOF+R
X 12 w
62% 74%
SOF+PR
X 12 w
58
Cirrhosis
Naïve Exp
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4 5 6 7
Summary of SVR rates in HCV G3 non cirrhosis HIV-& HIV+
Registrative studies: Fusion, Fission Positron, Valence, Lonestar, Ally 3, Gane et al AASLD 2014
SOF+R
X 24 w
92% 97%
146 45 75
A
B
C
D
PR SOFO
X 12 w
39
Naives
93%
SOF/DAC
X 12 w
88%
SOFO/R
X 24 w
137
PR SOFO
X 12 w
83% 97%
SOF/DAC
X 12 w
12
Experienced
SOF/LEDI
X 12 w
28
89%
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4 5 6
Summary of SVR rates in HCV G3 cirrhosis HIV-& HIV+
SOF+R
X 24 w
94% 59%
16 19 13
A
B
C
D
Naives
SOF/DAC
X 12 w
68%
109
SOFO/R
X 24 w
74
PR SOFO
X 12 w
83% 69%
SOF/DAC
X 12 w
12
Experienced
22
SOF/LEDI
X 12 w
72%
Registrative studies: Fusion, Fission Positron, Valence, Lonestar, Ally 3, Gane et al AASLD 2014
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4 5 6 7 8 9 10 11 12
Summary of SVR rates in HCV G4 HIV- & HIV+
Registrative studies;RESTORE III Neutrino,PEARL –I Osinusi et al AASlD 2014, Gamal E et al AASLD 2014
PR/SIME
X 24-48 w
86% 100%
2393 55 41
A
B
C
D
PR SOFO
X 12 w
33
SOF+R
X 24 w
Naïve Exp
Non Cirrhosis
89% 44%
86 32
SOF+R
X 24 w
8
Cirrhosis
NaïveExp
SOFO/
LEDI
X 12 w
14
2D
Abbvie
X 12 w
100% 93%
PR/SIME
X 24-48 w
50
SOF+R
X 24 w
94%
2D
Abbvie
X 12 w
SOFO/
LEDI
X 12 w
SOF+R
+ LEDI
X 24 w
100% 100% 91% 80%
1081
84%
PR
DAC
X 24 w
New drugs and strategies for HCV treatment
• Tools & strategies
• Upcoming Results
• The future
UNITY-1 Study Design (AI443-102)
Primary Endpoint
■SVR12 in treatment-naive patients
– HCV RNA < lower limit of quantitation (LLOQ) at posttreatment Week 12
– Demonstrate SVR12 is significantly greater than historical threshold of 79% (based on an analysis of sofosbuvir plus peginterferon/ribavirin data)
– Assessed using the Roche HCV COBAS TaqMan® test v2.0 (LLOQ, 25 IU/mL)
Treatment regimen
■Twice-daily, fixed-dose combination tablet (DCV-TRIO)
– DCV 30 mg / ASV 200 mg / BCV 75 mg
Treatment-naive(N = 312)
Follow-up
DCV/ASV/BCV FDC
DCV/ASV/BCV FDC
Treatment-experienced(N = 103)
Week 0 Week 24
(SVR12)
Week
12
Week 48
Poordad F et al. AASLD 2014. Poster
LB-7
Overall SVR12 Rate
SVR
12
, %a,
b
• Overall, SVR12 was achieved by 91% of HCV genotype 1-infected patients
a HCV RNA < LLOQ (25 IU/mL); patients with missing SVR12 data counted as treatment failures. b Error bars reflect 95% CI. Poordad F et al. AASLD 2014. Poster
LB-7
SVR12 Rates by Patient PopulationSV
R1
2, %
a,b
All GT 1a GT 1b All GT 1a GT 1b
Treatment-naive Treatment-experienced
a HCV RNA < LLOQ (25 IU/mL); patients with missing SVR12 data counted as treatment failures. b Error bars reflect 95% CI.
■ The SVR12 rate in treatment-naive HCV GT 1 patients (92%) was significantly higher than the historical threshold rate (79%)
– The lower bound 95% confidence interval (89%) exceeded the threshold value
■ A significantly higher SVR12 rate was observed in treatment-experienced HCV GT 1 patients (89%) compared with the historical threshold rate (48%)
■ High SVR12 rates (98–100%) were observed in treatment-naive and treatment-experienced patients infected with HCV GT 1b
Poordad F et al. AASLD 2014. Poster
LB-7
UNITY-2: Randomized, Double-Blind, Phase 3 Study
■ Primary efficacy assessment: SVR12
– HCV RNA < LLOQ (25 IU/mL) TD or TND at posttreatment Week 12
■ Twice-daily fixed-dose combination (FDC)
– DCV 30 mg / ASV 200 mg / BCV 75 mg
– With or without weight-based ribavirin twice-daily
Week 0 Week 24Week 12
Treatment-Naive
N = 112Follow-up
DCV/ASV/BCV FDC+ RBV
DCV/ASV/BCV FDC+ RBV
DCV/ASV/BCV FDC+ placebo for RBV
DCV/ASV/BCV FDC+ placebo for RBV
Treatment-Experienced
N = 90
Randomiz
e 1:1
Randomiz
e 1:1
TD, target detected; TND, target not detected
SVR12 (mITT)SVR12,
%
Naive Cohort Experienced Cohort
93 98a 87 93
DCV-TRIO DCV-TRIO
+ RBVDCV-TRIO DCV-TRIO
+ RBV
aOne patient with HCV RNA <LLOQ TND at end of therapy and posttreatment Week 4 had missing data at
posttreatment Week 12.
Error bars indicate 97.5% confidence intervals.
Key messages• HCV Eradication
• It is feasible in the single patient
• Early treatment improvement of quality of life and life expecyancy
• Late treatment : improved survival?
• Three very successful strategies: tailored treatment difficult access to treatment (price and complexity)
• Peg IFN based
• Sofosbuvir based
• Sofosbuvir free
• Lower efficacy in HCV G3 with poorer results in cirrhotics PEGIFN experienced --> add RBV + a DAA increase duration SOFO + NS5A + RBV x 24 weeks
• Future perspectives improvement in efficacy & access to treatment
• One pill (injection?) for all
• Short courses
• Price reduction
Where we go: the future 10 commandments for the magic drug
Courtesy of T Asselah.
COST REDUCTION (access program)
HIGH EFFICACY
LOW RESISTANCE (high genetic barrier)
FOR ALL GENOTYPES
SHORT DURATION
TOLERABILITY
PHARMACOKINETIC (low pill burden)
ONLY ORAL REGIMEN or 1 SHOT INJECTION (IFN free)
DRUG INTERACTION
AVAILABLE: CIRRHOSIS, ELD, HIV-HCV…
HCV ERADICATION WORLDWIDE
1
2
3
4
5
6
7
8
9
10